I am a pulmonologist and an Assistant Professor of Pediatrics at Vanderbilt University on the tenure track, with a master degree in patient-oriented research (Master of Science in Clinical Investigation, M.S.C.I.). I am at a critical point in career development, having just completed the master degree program but in need of further training in the disciplines of genetics, biostatistical genetics and epidemiology to achieve my immediate and long-term goals. My five-year goal is to become an expert in genetic epidemiology focused on the causes and mechanisms of heritable pulmonary arterial hypertension (HPAH), with particular emphasis on the sex hormone axis. My long-term goal is to become an independent physician-scientist capable of conducting large patient-oriented research studies and clinical trials that interpret and modulate the interaction of genetic, endogenous and environmental factors to generate health and disease; this includes, but is not limited to, HPAH. To successfully transition to independent extramural funding, I require continued strong mentorship. In this proposal, we delineate a training and research plan that benefits from my experienced mentor group, as well as the collaborative milieu of Vanderbilt and our Pulmonary Hypertension Research Group, to provide a comprehensive mentored educational and research experience. Primary Mentor Dr. James E. Loyd is an expert in the genetic epidemiology of inherited pulmonary diseases, having spent over 25 years developing the well-characterized research cohort that has been so vital to progress made in the study of HPAH, and in the successful transition of physician-scientists to independence. My mentoring committee now includes two new members with expertise in endocrinology, sex hormone metabolism and mentorship, to expand my mentored training influences. This proposal focuses my efforts on the investigation of gender, sex hormones and the development of pulmonary arterial hypertension (PAH). Most types of PAH, including HPAH due to mutations in bone morphogenic protein receptor type 2 (BMPR2)), predominantly affect women for unknown reasons, and our preliminary laboratory data support the central hypothesis that sex hormone variation modifies disease expression in HPAH, because elevated estrogen exposures promote disease. The mentoring, career development, and research plans dovetail to maximize my ability to test this hypothesis in a concise manner and provide a framework for future investigations. To test our hypothesis, we will study sex hormones using association and functional studies with biospecimens from BMPR2 mutation carriers of both genders. Aim 1 will determine whether mediators of estrogen and androgen activity are associated with HPAH. We hypothesize that higher estrogen activity (e.g., as represented by a lower ratio of 2-hydroxyestrogens: 161-hydroxyestrogens) will be associated with increased risk of HPAH and younger age at diagnosis. Aim 2 will determine whether estrogen-enhancing and androgen-diminishing genotypes are associated with HPAH. We hypothesize that estrogen-enhancing and testosterone-diminishing genotypes increase the risk of developing HPAH among BMPR2 mutation carriers. Aim 3 will determine whether sex hormones regulate BMPR2 gene expression in normal pulmonary microvascular endothelial cells and in cell lines derived from BMPR2 mutation carriers. We hypothesize that estrogens will decrease BMPR2 expression, while androgens will increase BMPR2 expression (low BMPR2 expression associates with HPAH). In completing the proposed training and research plans, I will gain the necessary expertise to design, conduct, and analyze multi-disciplinary research studies involving complicated genetic factors. This will allow me to compete effectively for future NIH support and propel me to an independent career in patient-oriented research.